METTL3 and N6-Methyladenosine Promote Homologous Recombination-Mediated Repair of DSBs by Modulating DNA-RNA Hybrid Accumulation.

Double-strand breaks (DSBs) are the most deleterious DNA lesions, which, if left unrepaired, may lead to genome instability or cell death. Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. Phosphorylated METTL3 is then localized to DNA damage sites, where it methylates the N6 position of adenosine (m6A) in DNA damage-associated RNAs, which recruits the m6A reader protein YTHDC1 for protection. In this way, the METTL3-m6A-YTHDC1 axis modulates accumulation of DNA-RNA hybrids at DSBs sites, which then recruit RAD51 and BRCA1 for homologous recombination (HR)-mediated repair. METTL3-deficient cells display defective HR, accumulation of unrepaired DSBs, and genome instability. Accordingly, depletion of METTL3 significantly enhances the sensitivity of cancer cells and murine xenografts to DNA damage-based therapy. These findings uncover the function of METTL3 and YTHDC1 in HR-mediated DSB repair, which may have implications for cancer therapy.

Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma.

Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRT‒PCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.

Somatic 9p24.1 alterations in HPV- head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity.

Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus-negative (HPV-) head and neck squamous cancer (HNSC), associated with an immune-cold tumor microenvironment (TME) signal, and recent evidence suggested that this TME-cold phenotype was greatly enhanced with 9p21 deletion size, notably encompassing band 9p24.1 (3). Here, we report multi-omic, -threshold and continuous-variable dissection of 9p21 and 9p24 loci (including depth and degree of somatic alteration of each band at each locus, and each gene at each band) and TME of four HPV- HNSC cohorts. Preferential 9p24 deletion, CD8 T-cell immune-cold associations were observed, driven by 9p24.1 loss, and in turn by an essential telomeric regulatory gene element, JAK2-CD274. Surprisingly, same genetic region gains were immune hot. Related 9p21-TME analyses were less evident. Inherent 9p-band-level influences on anti-PD1 ICT survival rates, coincident with TME patterns, were also observed. At a 9p24.1 whole-transcriptome expression threshold of 60th percentile, ICT survival rate exceeded that of lower expression percentiles and of chemotherapy; below this transcript threshold, ICT survival was inferior to chemotherapy, the latter unaffected by 9p24.1 expression level (P-values < 0.01, including in a PD-L1 immunohistochemistry-positive patient subgroup). Whole-exome analyses of 10 solid-tumor types suggest that these 9p-related ICT findings could be relevant to squamous cancers, in which 9p24.1 gain/immune-hot associations exist.

Ramucirumab in combination with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma: a single-centre, phase 1/2 trial.

BACKGROUND: VEGF, a key mediator of angiogenesis and resistance to immunotherapy, is overexpressed in head and neck squamous cell carcinoma (HNSCC). We aimed to determine the recommended phase 2 dose of ramucirumab, a selective VEGFR2 inhibitor, given with pembrolizumab and the objective response rate of this combination as first-line treatment for recurrent or metastatic HNSCC. METHODS: In this single-centre, phase 1/2 trial, which was done at Washington University (St Louis, MO, USA), eligible patients were aged 18 years or older with incurable recurrent or metastatic HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. Patients in phase 2 were required to have had no previous systemic therapy for recurrent or metastatic disease. In a dose de-escalation phase 1 design, patients received ramucirumab (starting dose 10 mg/kg given intravenously) and pembrolizumab (200 mg intravenously) on day 1 of each 21-day cycle. The recommended phase 2 dose of ramucirumab was defined as the highest dose at which one or fewer of three patients had dose-limiting toxicity during cycle one (primary endpoint of phase 1). In a Simon's two-stage phase 2 design, patients received the recommended phase 2 dose of ramucirumab and pembrolizumab. Tumour response (primary endpoint of phase 2) was assessed by Response Evaluation Criteria in Solid Tumours (version 1.1). We hypothesised that there would be an objective response rate of 32% or higher (null ≤13%). Eight or more responses among 33 evaluable patients (those with at least one response assessment) was evidence for activity (80% power; one-sided α=0·05). Analyses were done per protocol. The trial is registered with ClinicalTrials.gov, NCT03650764, and is closed to enrolment. FINDINGS: Between June 18, 2019, and Feb 11, 2021, three patients enrolled and were treated in phase 1 and 37 patients in phase 2. Median age of all patients was 64 years (IQR 59-72). 36 (90%) of 40 patients were men and four (10%) were women, and 36 (90%) patients were White, three (8%) were Black or African American, and one (3%) was Asian. In phase 1, no dose-limiting toxicity event occurred. The recommended phase 2 dose of ramucirumab was 10 mg/kg. Median follow-up for patients on phase 2 was 14·8 months (IQR 4·9-31·0). In phase 2, 18 (55%; 95% CI 38-70) of 33 evaluable patients had an objective response, including confirmed complete response in 11 patients, confirmed partial response in six patients, and unconfirmed partial response in one patient. The most common grade 3 or worse adverse events were dysphagia (14 [38%] of 37 patients), lung infection (11 [30%]), lymphocyte count decrease (ten [27%]), hypophosphataemia (nine [24%]), and hypertension (eight [22%]). No treatment-related deaths were recorded. INTERPRETATION: Ramucirumab and pembrolizumab were safe to administer to patients with recurrent or metastatic HNSCC, and the objective response rate with this combination as first-line treatment for recurrent or metastatic HNSCC was favourable. Further studies of ramucirumab and pembrolizumab in patients with recurrent or metastatic HNSCC are warranted. FUNDING: Lilly and the Joseph Sanchez Foundation.

Resistance of HNSCC cell models to pan-FGFR inhibition depends on the EMT phenotype associating with clinical outcome.

BACKGROUND: Focal adhesion signaling involving receptor tyrosine kinases (RTK) and integrins co-controls cancer cell survival and therapy resistance. However, co-dependencies between these receptors and therapeutically exploitable vulnerabilities remain largely elusive in HPV-negative head and neck squamous cell carcinoma (HNSCC). METHODS: The cytotoxic and radiochemosensitizing potential of targeting 10 RTK and ß1 integrin was determined in up to 20 3D matrix-grown HNSCC cell models followed by drug screening and patient-derived organoid validation. RNA sequencing and protein-based biochemical assays were performed for molecular characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. RESULTS: Fibroblast growth factor receptor (FGFR 1-4) targeting exhibited the strongest cytotoxic and radiosensitizing effects as monotherapy and combined with ß1 integrin inhibition, exceeding the efficacy of the other RTK studied. Pharmacological pan-FGFR inhibition elicited responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence analysis revealed a mesenchymal-to-epithelial transition (MET) in sensitive cell models, whereas resistant cell models exhibited a partial epithelial-to-mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid-dependently. Transferring the EMT-associated transcriptomic profiles to HNSCC patient cohorts not only demonstrated their prognostic value but also provided a conclusive validation of the presence of EGFR-related vulnerabilities that can be strategically exploited for therapeutic interventions. CONCLUSIONS: This study demonstrates that pan-FGFR inhibition elicits a beneficial radiochemosensitizing and a detrimental radioprotective potential in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically.

Effect of preoperative programmed death-1 or programmed death ligand-1 immune check point inhibition on complications after surgery for primary head and neck cancer.

BACKGROUND: There is sparse literature on the effect of preoperative immunotherapy on complications after surgery for primary head and neck squamous cell carcinoma (HNSCC). The objectives are to compare complication rates in patients receiving surgery with and without neoadjuvant immune checkpoint inhibitors (nICI) for primary HNSCC and to evaluate factors associated with increased odds of surgical complications. METHODS: A retrospective review of patients who underwent ablation and free flap reconstruction or transoral robotic surgery (TORS) for primary HNSCC between 2017-2021 was conducted. Complications were compared between patients who underwent surgery with or without nICI before and after propensity score matching. Regression analysis to estimate odds ratios was performed. RESULTS: A total of 463 patients met inclusion criteria. Free flap reconstruction constituted 28.9% of patients and TORS constituted 71.1% of patients. nICI was administered in 83 of 463 (17.9%) patients. There was no statistically significant difference in surgical, medical, or overall complications between patients receiving surgery with or without nICI. In the unmatched cohort, multivariable model identified non-White race, former/current smoking history, free flap surgery, and perineural invasion as factors significantly associated with increased complications. In the matched cohort, multivariable model identified advanced age and free flap surgery as factors significantly associated with increased complications. PLAIN LANGUAGE SUMMARY: It is safe to give immunotherapy before major surgery in patients who have head and neck cancer. Advanced age, non-White race, current/former smoking, free flap surgery, and perineural invasion may be associated with increased the odds of surgical complications.

DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.

BACKGROUND: Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood. METHODS: Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects. RESULTS: Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis. CONCLUSION: Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.

B-cell infiltration is associated with survival outcomes following programmed cell death protein 1 inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand 1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC. PATIENTS AND METHODS: NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes. RESULTS: High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively). CONCLUSIONS: Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression.

Retrospective assessment of neoadjuvant camrelizumab combined with induction chemotherapy: efficacy in laryngeal preservation for advanced hypopharyngeal and laryngeal squamous cell carcinoma.

BACKGROUND: Hypopharyngeal and laryngeal squamous cell carcinoma (SCC) account for 25-30% of head and neck SCC. Total laryngectomy, while effective, compromises the quality of life. Immune checkpoint inhibitors such as Camrelizumab offer potential in laryngeal preservation. The study investigated Camrelizumab combined with TP regimen as a neoadjuvant therapy for laryngeal preservation in advanced hypopharyngeal and laryngeal SCC. METHODS: A retrospective study was conducted at Sun Yat-sen University Cancer Center on patients diagnosed with locally advanced SCC of the hypopharynx and larynx from October 1, 2019, to October 25, 2022. The efficacy of a first-line treatment combining Camrelizumab (200 mg) and TP regimen (Albumin-bound paclitaxel at 260 mg/m2 and Cisplatin at 60 mg/m2) was evaluated using RECIST 1.1 criteria. Outcomes included overall survival (OS), progression-free survival (PFS), laryngectomy-free survival (LFS), and response rates. RESULTS: Of the 71 included patients, the median age was 60.7 years. Post the first-line treatment, 90.1% demonstrated an overall response. The one-year and two-year OS rates were 91.5% and 84.3%, respectively. One-year and two-year PFS rates were 92.9% and 83.9%, respectively, with LFS at 85.6% and 73.2%. The initial T4 stage as significantly associated with reduced OS and LFS. Skin reaction was the predominant adverse event. CONCLUSION: The Camrelizumab-TP regimen demonstrated promising results for advanced hypopharyngeal/laryngeal SCC patients, exhibiting high response rates, OS, and LFS, positioning it as a potential primary option for laryngeal preservation. Further comprehensive, randomized controlled studies are imperative to validate these initial observations and elucidate the regimen's full clinical efficacy in optimizing laryngeal outcomes.

PD-L1-positive circulating endothelial progenitor cells associated with immune response to PD-1 blockade in patients with head and neck squamous cell carcinoma.

A number of the inhibitors against programmed death protein 1 (PD-1) have been approved to treat recurrent or metastatic squamous cell carcinoma of head and neck (HNSCC). The interaction between PD-1 and its ligand (PD-L1) serves as an immune checkpoint that governs cytotoxic immune effectors against tumors. Numerous clinical trials of PD-1/PD-L1 inhibitors have so far been discordant about having sufficient PD-L1 expression in the tumor as a prerequisite for a successful anti-PD-1 treatment. On the other hand, vascular endothelial cells modulate immune activities through PD-L1 expression, and thus it is possible that the expressions of circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CPCs) could affect antitumor immunity as well as neoangiogenesis. Here we investigated the potential involvement of PD-L1+ CECs and PD-L1+ CPCs in PD-1 blockade treatments for HNSCC patients. We measured CD8+ T cells, CECs, and CPCs in the peripheral blood of the HNSCC patients treated by anti-PD-1 therapies. We found that their PD-L1+ CPC expression before anti-PD1 therapies was strongly correlated with treatment responses and overall survival. Moreover, if the first infusion of PD-1 inhibitors reduced ≥ 50% PD-L1+ CPCs, a significantly better outcome could be predicted. In these patients as well as in an animal model of oral cancer, Pd-l1+ CPC expression was associated with limited CD8+ T-cell infiltration into the tumors, and anti-PD-1 treatments also targeted Pd-l1+ CPCs and increased CD8+ T-cell infiltration. Our results highlight PD-L1+ CPC as a potential regulator in the anti-PD-1 treatments for HNSCC.

Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR). METHODS: Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed. RESULTS: Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48-1.72) and 0.69 (0.39-1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs. CONCLUSIONS: bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME. Trial registration ClinicalTrials.gov identifier NCT02551159.

The potential roles of antibody-drug conjugates in head and neck squamous cell carcinoma.

PURPOSE OF REVIEW: To summarize the actual antibody-drug conjugates (ADCs) tested for patients with advanced head and neck squamous cell carcinoma (HNSCC), outlining the results of safety and efficacy through published clinical trials. RECENT FINDINGS: ADCs combine the specificity of mAbs with the cytotoxic drug (known as payload) via a chemical linker and it is designed to selectively deliver the ultratoxic payload directly to the target cancer cells. To date, various ADCs have been investigated in multiple solid malignancies and others are in clinical development. In this study, we provide an overview of the structure and biology of ADC and we review recent clinical experience with the ADC in patients with advanced HNSCC, followed by a brief discussion of the evolvement of ADC conception, drug resistance and future perspectives. SUMMARY: ADC strategy is emerging as a potential active treatment in previously treated patients with advanced HNSCC. However, the recent improvement in the bioengineering of ADC and a better comprehension of sequencing and association strategies could provide more benefit to HNSCC patients in need of innovative therapy.

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA-mediated modulation of the RIPK1-FADD-Caspase 8 complex.

Tanshinone IIA (Tan IIA), a main active ingredient of salvia miltiorrhiza, has a wide range of antitumor effects, while its specific role and mechanism in head and neck squamous cell carcinomas (HNSCC) is not fully understood. Totally 59 primary HNSCC patients underwent two courses of induction chemotherapy before surgery. The association between expression of Fas-Associated Death Domain (FADD) and receptor interacting protein kinase 1 (RIPK1) and chemotherapy resistance and survival were evaluated. The cell counting kit-8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments. The quantitative real-time reverse-transcription polymerase chain reaction, Western blot analysis and flow cytometry were used. FADD and RIPK1 expressions were differentially expressed in Chemosensitive and drug-resistant patients. Furthermore, patients with tumors exhibiting high expression of FADD and RIPK1 had significantly greater risk for chemoresistance and mortality than patients with tumors that had low levels of these proteins. Moreover, Tan IIA reduced the expression of RIPK1 and FADD in HNSCC chemoresistant cell lines, which could increase the chemosensitivity of cisplatin and promote apoptosis. Overexpression of RIPK1 led to attenuation of therapeutic effects of Tan IIA, which were mainly realized through regulation of the RIPK1-FADD-Caspase 8 complex. This study is the first to demonstrate the clinical value and role of FADD and RIPK1 in the treatment of HNSCC. This work establishes the proapoptotic effects of Tan IIA and its potential to enhance chemosensitivity in HNSCC by modulating the RIPK1-FADD-Caspase 8 complex.

Tumor mutational burden predictability in head and neck squamous cell carcinoma patients treated with immunotherapy: systematic review and meta-analysis.

BACKGROUND: Tumor mutational burden (TMB) has been demonstrated to predict the response to immune checkpoint inhibitors (ICIs) in various cancers. However, the role of TMB in head and neck squamous cell carcinoma (HNSCC) has not yet been specifically addressed. Since HNSCC patients exhibit a rather limited response to ICIs, there is an unmet need to develop predictive biomarkers to improve patient selection criteria and the clinical benefit of ICI treatment. METHODS: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. HNSCC cohort studies were selected when TMB prior to ICI treatment was evaluated, TMB cutoff value was available, and the prognostic value of TMB was evaluated by time-to-event survival analysis. A total of 11 out of 1960 articles were analyzed, including 1200 HNSCC patients. RESULTS: The results showed that those patients harboring high TMB exhibited a significantly superior overall response rate (OR = 2.62; 95% CI 1.74-3.94; p < 0.0001) and a survival advantage (HR = 0.53; 95% CI 0.39-0.71; p < 0.0001) after ICI treatment. CONCLUSION: This is the first meta-analysis to demonstrate a higher response and clinical benefit from ICI therapy in HNSCC patients with high TMB.

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.

Antibiotics May Interfere with Nivolumab Efficacy in Patients with Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Patients with the head and neck squamous cell carcinoma (SCC) are often treated with immune checkpoint inhibitors (ICIs). Recently, antibiotic intake was reported to lower the efficacy of ICIs in patients with several types of cancers. However, it is unclear if antibiotics affect the efficacy of ICIs in patients with head and neck SCC. We retrospectively assessed the influence of antibiotics on the treatment efficacy of nivolumab, an ICI, in patients with head and neck SCC. METHODS: We reviewed the medical records of patients with head and neck SCC treated with nivolumab at the Department of Medical Oncology, Tohoku University Hospital, between 2017 and 2021. Patients who received oral or intravenous antibiotics from a month before the day of nivolumab initiation to the day of the first imaging evaluation of ICI efficacy were assigned to the antibiotic-treated group. The remaining patients were assigned to the antibiotic-untreated group. The response rate (RR), progression-free survival (PFS), and overall survival time (OS) of both groups were compared. RESULTS: Forty-five patients were assigned to the antibiotic-treated group and 19 to the antibiotic-untreated group. The RR, median PFS, and median OS of the antibiotic-treated group were 23.7%, 3.2 months (95% confidential interval [CI]: 2.0-4.1), and 8.4 months (95% CI: 5.3-15.1) and those of the antibiotic-untreated group were 42.1%, 5.8 months (95% CI: 2.3-16.7), and 18.4 months (95% CI: 6.2-23.1), respectively. The PFS of the antibiotic-untreated group was significantly longer than that of the antibiotic-treated group. CONCLUSION: Our findings indicate that antibiotic treatment significantly shortens the PFS with nivolumab therapy in patients with head and neck SCC.

Pembrolizumab-based first-line treatment for PD-L1-positive, recurrent or metastatic head and neck squamous cell carcinoma: a retrospective analysis.

BACKGROUND: The KEYNOTE-048 trial showed that pembrolizumab-based first-line treatment for R/M HNSCC led to improved OS in the PD-L1 CPS ≥ 1 population when compared to the EXTREME regimen. However, the R/M HNSCC real-world population is generally frailer, often presenting with multiple comorbidities, worse performance status and older age than the population included in phase III clinical trials. METHODS: This is a retrospective, single-centre analysis of patients with R/M HNSCC treated with pembrolizumab-based first-line treatment. RESULTS: From February 2021 to March 2023, 92 patients were treated with pembrolizumab-based first-line treatment. Patients treated with pembrolizumab-based chemoimmunotherapy had better ECOG PS and younger age than those treated with pembrolizumab monotherapy. Median PFS and OS were 4 months and 8 months, respectively. PFS was similar among patients treated with pembrolizumab-based chemoimmunotherapy and pembrolizumab monotherapy, while patients treated with pembrolizumab monotherapy had worse OS (log-rank p =.001, HR 2.7). PFS and OS were improved in patients with PD-L1 CPS > = 20 (PFS: log-rank p =.005, HR 0.50; OS: log-rank p =.04, HR 0.57). Patients with higher ECOG PS scores had worse PFS and OS (PFS, log-rank p =.004; OS, log-rank p = 6e-04). In multivariable analysis, ECOG PS2 was associated with worse PFS and OS. CONCLUSIONS: PFS in our real-world cohort was similar to the KEYNOTE-048 reference while OS was numerically inferior. A deeper understanding of clinical variables that might affect survival outcomes of patients with R/M HNSCC beyond ECOG PS and PD-L1 CPS is urgently needed.

p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90RSK in cisplatin resistance and identify the combination of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therapeutic strategy to overcome cisplatin resistance. In addition, we have identified TMEM16A expression as a potential upstream regulator of p90RSK through the ERK pathway and a biomarker of response to p90RSK targeted therapy in the context of cisplatin resistance.

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical ß-catenin pathway.

BACKGROUND: 5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection. METHODS: 5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy. RESULTS: In this study, the WNT/ß-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells. CONCLUSIONS: These data underscored the activation of the WNT/ß-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.

HOXA1 silencing inhibits cisplatin resistance of oral squamous cell carcinoma cells via IκB/NF-κB signaling pathway.

The resistance of oral squamous cell carcinoma (OSCC) cells to cisplatin remains a tough nut to crack in OSCC therapy. Homeobox A1 (HOXA1) overexpression has been detected in head and neck squamous carcinoma (HNSC). Accordingly, this study aims to explore the potential role and mechanism of HOXA1 on cisplatin resistance in OSCC. The expression of HOXA1 in HNSC and its role in overall survival (OS) rate of OSCC patients were analyzed by bioinformatic analysis. Following transfection as needed, OSCC cells were induced by different concentrations of cisplatin, and the cell viability and apoptosis were evaluated by cell counting kit-8 and flow cytometry assays. The mRNA and protein expression levels of HOXA1 and the phosphorylation of IκBα and p65 were determined by real-time quantitative PCR and western blot. HOXA1 expression level was upregulated in HNSC tissues and OSCC cells. Overexpressed HOXA1 was correlated with a low OS rate of OSCC patients. Cisplatin exerted an anti-cancer effect on OSCC cells. HOXA1 silencing or cisplatin suppressed OSCC cell viability, boosted the apoptosis, and repressed the phosphorylation of IκBα and p65. Intriguingly, the combination of HOXA1 silencing and cisplatin generated a stronger anti-cancer effect on OSCC cells than their single use. HOXA1 silencing attenuates cisplatin resistance of OSCC cells via IκB/NF-κB signaling pathway, hinting that HOXA1 is a biomarker associated with OSCC and HOXA1 silencing can enhance the sensitivity of OSCC cells to cisplatin.